{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T16:22:46Z","timestamp":1762100566816},"reference-count":26,"publisher":"Portland Press Ltd.","issue":"3","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2006,9,15]]},"abstract":"<jats:p>The neurodegenerative disorder FRDA (Friedreich's ataxia) results from a deficiency in frataxin, a putative iron chaperone, and is due to the presence of a high number of GAA repeats in the coding regions of both alleles of the frataxin gene, which impair protein expression. However, some FRDA patients are heterozygous for this triplet expansion and contain a deleterious point mutation on the other allele. In the present study, we investigated whether two particular FRDA-associated frataxin mutants, I154F and W155R, result in unfolded protein as a consequence of a severe structural modification. A detailed comparison of the conformational properties of the wild-type and mutant proteins combining biophysical and biochemical methodologies was undertaken. We show that the FRDA mutants retain the native fold under physiological conditions, but are differentially destabilized as reflected both by their reduced thermodynamic stability and a higher tendency towards proteolytic digestion. The I154F mutant has the strongest effect on fold stability as expected from the fact that the mutated residue contributes to the hydrophobic core formation. Functionally, the iron-binding properties of the mutant frataxins are found to be partly impaired. The apparently paradoxical situation of having clinically aggressive frataxin variants which are folded and are only significantly less stable than the wild-type form in a given adverse physiological stress condition is discussed and contextualized in terms of a mechanism determining the pathology of FRDA heterozygous.<\/jats:p>","DOI":"10.1042\/bj20060345","type":"journal-article","created":{"date-parts":[[2006,8,31]],"date-time":"2006-08-31T10:45:57Z","timestamp":1157021157000},"page":"605-611","update-policy":"http:\/\/dx.doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Conformational stability of human frataxin and effect of Friedreich's ataxia-related mutations on protein folding"],"prefix":"10.1042","volume":"398","author":[{"given":"Ana\u00a0R.","family":"Correia","sequence":"first","affiliation":[{"name":"Instituto Tecnologia Qu\u00edmica e Biol\u00f3gica, Universidade Nova de Lisboa, Av. Rep\u00fablica 127, 2780-756 Oeiras, Portugal"}]},{"given":"Salvatore","family":"Adinolfi","sequence":"additional","affiliation":[{"name":"National Institute for Medical Research, Medical Research Council, London, U.K."}]},{"given":"Annalisa","family":"Pastore","sequence":"additional","affiliation":[{"name":"National Institute for Medical Research, Medical Research Council, London, U.K."}]},{"given":"Cl\u00e1udio\u00a0M.","family":"Gomes","sequence":"additional","affiliation":[{"name":"Instituto Tecnologia Qu\u00edmica e Biol\u00f3gica, Universidade Nova de Lisboa, Av. Rep\u00fablica 127, 2780-756 Oeiras, Portugal"}]}],"member":"288","published-online":{"date-parts":[[2006,8,29]]},"reference":[{"key":"2021112213415687200_B1","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1001\/archneur.56.10.1201","article-title":"Molecular pathogenesis of Friedreich ataxia","volume":"56","author":"Pandolfo","year":"1999","journal-title":"Arch. Neurol."},{"key":"2021112213415687200_B2","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/334248a0","article-title":"Mapping of mutation causing Friedreich's ataxia to human chromosome 9","volume":"334","author":"Chamberlain","year":"1988","journal-title":"Nature (London)"},{"key":"2021112213415687200_B3","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/S0014-5793(03)01498-4","article-title":"Mitochondrial functional interactions between frataxin and Isu1p, the iron\u2013sulfur cluster scaffold protein, in Saccharomyces cerevisiae","volume":"557","author":"Ramazzotti","year":"2004","journal-title":"FEBS Lett."},{"key":"2021112213415687200_B4","doi-asserted-by":"crossref","first-page":"2635","DOI":"10.1093\/hmg\/11.21.2635","article-title":"A non-essential function for yeast frataxin in iron\u2013sulfur cluster assembly","volume":"11","author":"Duby","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"2021112213415687200_B5","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1038\/sj.embor.embor918","article-title":"An interaction between frataxin and Isu1\/Nfs1 that is crucial for Fe\/S cluster synthesis on Isu1","volume":"4","author":"Gerber","year":"2003","journal-title":"EMBO Rep."},{"key":"2021112213415687200_B6","doi-asserted-by":"crossref","first-page":"25943","DOI":"10.1074\/jbc.C400107200","article-title":"Frataxin-mediated iron delivery to ferrochelatase in the final step of heme biosynthesis","volume":"279","author":"Yoon","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2021112213415687200_B7","doi-asserted-by":"crossref","first-page":"6078","DOI":"10.1021\/ja027967i","article-title":"Iron\u2013sulfur cluster biosynthesis: characterization of frataxin as an iron donor for assembly of [2Fe\u20132S] clusters in ISU-type proteins","volume":"125","author":"Yoon","year":"2003","journal-title":"J. Am. Chem. Soc."},{"key":"2021112213415687200_B8","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1126\/science.1098991","article-title":"Frataxin acts as an iron chaperone protein to modulate mitochondrial aconitase activity","volume":"305","author":"Bulteau","year":"2004","journal-title":"Science"},{"key":"2021112213415687200_B9","doi-asserted-by":"crossref","first-page":"31340","DOI":"10.1074\/jbc.M303158200","article-title":"Yeast frataxin sequentially chaperones and stores iron by coupling protein assembly with iron oxidation","volume":"278","author":"Park","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2021112213415687200_B10","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1002\/1531-8249(199902)45:2<200::AID-ANA10>3.0.CO;2-U","article-title":"Friedreich's ataxia: point mutations and clinical presentation of compound heterozygotes","volume":"45","author":"Cossee","year":"1999","journal-title":"Ann. Neurol."},{"key":"2021112213415687200_B11","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1126\/science.271.5254.1423","article-title":"Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion","volume":"271","author":"Campuzano","year":"1996","journal-title":"Science"},{"key":"2021112213415687200_B12","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1093\/hmg\/11.16.1865","article-title":"A structural approach to understanding the iron-binding properties of phylogenetically different frataxins","volume":"11","author":"Adinolfi","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"2021112213415687200_B13","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1016\/S0969-2126(00)00158-1","article-title":"Towards a structural understanding of Friedreich's ataxia: the solution structure of frataxin","volume":"8","author":"Musco","year":"2000","journal-title":"Structure"},{"key":"2021112213415687200_B14","doi-asserted-by":"crossref","first-page":"30753","DOI":"10.1074\/jbc.C000407200","article-title":"Crystal structure of human frataxin","volume":"275","author":"Dhe-Paganon","year":"2000","journal-title":"J. Biol. Chem."},{"key":"2021112213415687200_B15","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1023\/A:1008398832619","article-title":"Assignment of the 1H, 15N, and 13C resonances of the C-terminal domain of frataxin, the protein responsible for Friedreich ataxia","volume":"15","author":"Musco","year":"1999","journal-title":"J. Biomol. NMR"},{"key":"2021112213415687200_B16","doi-asserted-by":"crossref","first-page":"6511","DOI":"10.1021\/bi036049+","article-title":"The factors governing the thermal stability of frataxin orthologues: how to increase a protein's stability","volume":"43","author":"Adinolfi","year":"2004","journal-title":"Biochemistry"},{"key":"2021112213415687200_B17","first-page":"183","article-title":"Urea and guanidine hydrochloride denaturation curves","volume":"40","author":"Shirley","year":"1995","journal-title":"Methods Mol. Biol."},{"key":"2021112213415687200_B18","first-page":"311","article-title":"Measuring the conformational stability of proteins","volume-title":"Protein Structure: a Practical Approach","author":"Pace","year":"1990"},{"key":"2021112213415687200_B19","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1006\/jmbi.1998.1760","article-title":"Conformational stability and thermodynamics of folding of ribonucleases Sa, Sa2 and Sa3","volume":"279","author":"Pace","year":"1998","journal-title":"J. Mol. Biol."},{"key":"2021112213415687200_B20","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.jmb.2003.11.056","article-title":"Protein stability in nanocages: a novel approach for influencing protein stability by molecular confinement","volume":"336","author":"Bolis","year":"2004","journal-title":"J. Mol. Biol."},{"key":"2021112213415687200_B21","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/0003-2697(81)90474-7","article-title":"Fluorescence quenching studies with proteins","volume":"114","author":"Eftink","year":"1981","journal-title":"Anal. Biochem."},{"key":"2021112213415687200_B22","first-page":"262","article-title":"Proteins in solution and in membranes: aqueous solubility","volume-title":"Proteins: Structure and Molecular Properties","author":"Creighton","year":"1996"},{"key":"2021112213415687200_B23","doi-asserted-by":"crossref","first-page":"299","DOI":"10.18388\/abp.2004_3573","article-title":"Probing protein structure by limited proteolysis","volume":"51","author":"Fontana","year":"2004","journal-title":"Acta Biochim. Pol."},{"key":"2021112213415687200_B24","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1016\/j.str.2004.08.012","article-title":"Solution structure of the bacterial frataxin ortholog, CyaY: mapping the iron binding sites","volume":"12","author":"Nair","year":"2004","journal-title":"Structure"},{"key":"2021112213415687200_B25","doi-asserted-by":"crossref","first-page":"16254","DOI":"10.1021\/bi0488193","article-title":"Yeast frataxin solution structure, iron binding, and ferrochelatase interaction","volume":"43","author":"He","year":"2004","journal-title":"Biochemistry"},{"key":"2021112213415687200_B26","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1016\/0022-2836(88)90471-8","article-title":"Aromatic rings act as hydrogen bond acceptors","volume":"201","author":"Levitt","year":"1988","journal-title":"J. Mol. Biol."}],"container-title":["Biochemical Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/398\/3\/605\/649510\/bj3980605.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/398\/3\/605\/649510\/bj3980605.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,22]],"date-time":"2021-11-22T14:58:56Z","timestamp":1637593136000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/biochemj\/article\/398\/3\/605\/42442\/Conformational-stability-of-human-frataxin-and"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,8,29]]},"references-count":26,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2006,9,15]]}},"URL":"https:\/\/doi.org\/10.1042\/bj20060345","relation":{},"ISSN":["0264-6021","1470-8728"],"issn-type":[{"value":"0264-6021","type":"print"},{"value":"1470-8728","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,8,29]]}}}